Novel method and compositions

ABSTRACT

An improvement in the method of treating paralysis agitans by administration of 3,4-dihydroxy-phenyl-1-alanine, its hydrates and salts thereof is disclosed, which comprises administering it concurrently with a benzodiazepine compound having sedativehypnotic and anxiolytic activity. Disclosed also are therapeutic compositions which comprise mixtures of 3,4-dihydroxyphenyl-1alanine with benzodiazepines. The therapeutic compositions are useful in the treatment of humans afflicted with paralysis agitans.

United States Patent [191 Friis, Jr. et al.

NOVEL METHOD AND COMPOSITIONS Inventors: Walter Friis, Jr., Bangor; Allan D. Rudzik, Kalamazoo, both of Mich.

Assignee: The Upjohn Company, Kalamazoo,

Mich. Filed: Oct, 29,1974

Appl. No.: 518,451

Related US. Application Data Continuation of Ser. No. 386,564, Aug. 8, 19 73, abandoned.

US. Cl. 424/244; 424/251; 424/263;

424/269; 424/275; 424/319 Int, Cl. A61K 31/33; A61K 31/195 Field of Search 424/244, 319

References Cited I UNITED STATES PATENTS 10/1972 Bartholini 424/319 4/1973 Cash et al. 424/303 10/1973 Bayne 424/319 Dec. 23, 1975 OTHER PUBLICATIONS Conn, Current Therapy (1970), pp. 662-663.

Physicians Desk Reference (P.D.R.), 1971, pp. 1122-1123.

Primary Examinen-Stanley J. Friedman Attorney, Agent, or Firm-John J. Killingerj Roman Saliwanchik 57 ABSTRACT 3,4-dihydroxyphenyl-l-alanine with benzodiaze pines.

The therapeutic-compositions are'useful in the treatment of humans afflicted with paralysis agitans.

2 Claims, No Drawings NOVEL METHOD AND COMPOSITIONS This is a continuation of application Ser. No. 386,564, filed Aug. 8, 1973, now abandoned.

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention concerns an improvement in the treatment of humans afflicted with paralysis agitans by administration of 3,4-dihydroxyphenyl-l-alanine. More particularly, the invention concerns potentiation of 3.4-dihydroxyphenyl-l-alanine with a benzodiazepine adjuvant.

2. Description of the Prior Art A combination of 3,4-dihydroxyphenyl-l-alanine with a tricyclic antidepressant such as -[3-(dimethylamino)propyl]-10, l l-dihydro-5H-dibenz[b,f]azepine and an N-substituted-N -(2,3-4-trihydroxybenzyl)-hydrazine is disclosed in U.S. Pat. No. 3,646,213 as an effective antidepressant composition.

The use of 3,4-dihydroxyphenyl-l-alanine, hydrates thereof and pharmaceutically acceptable acid addition salts thereof, to treat humans afflicted with paralysis agitans (also referred to alternatively in the literature as shaking palsy, Parkinsonism, Parkinsons syndrome" and Parkinsons disease) has been well documented; see, for example, Cotzias et al., Long-Term Efl'ects of DOPA on Parkinsonism, 3rd Symposium on Parkinsons Disease. Edinburgh, 1968, Vol. 1, Gillingham and Donaldson, Editors, pps. 178-181, London, E. and S. Livingston, Publ. (1969); DuVoisin et al., 3rd Symposium on Parkinsons Disease, supra, pps. 185-192; Van Woert et al., N. Eng. Jour. Med, 276, 374-9, (1967) and Siegfried et al.,-Phann Clin., 2, 23-6, (1969); U.S. Pat. Nos. 3,557,292 and 3,701,829. The dosage of 3,4-dihydroxyphenyl-l-alanine required to alleviate the symptoms of paralysis agitans ranges from 5 to 8 grams daily for the average adult patient. At therapeutic dosage levels, a number of undesirable peripheral side effects occur, such as for example, nausea, involuntary movements (choreifonn nods, twitchs, grimaces, weaving gait and shuffles), somnolence, depression and increased libido.

Cash, et al. disclosed in U.S. Pat. No. 3,729,563 that the high doses of 3,4-dihydroxy-l-alanine required to treat Parkinsonism could be reduced by administering it in conjunction with doses of gallic acid. Gallic acid and its derivatives themselves have the property of alleviating involuntary muscle activity for short periods of time.

Siegfried et al., Ger. Med. Monthly, 15, 315, (1970), and Siegfried et al., supra, reported that the dosage of 3,4-dihydroxyphenyll -alanine required to alleviate the akinesiatic symptoms of paralysis agitans could be reduced to as little as one-tenth of the usual dosage by administering it in conjunction with a decarboxylase Pharm. Clin., supra). The decarboxylase inhibitors are also not without their limitations in use. For example, they are generally not advisably administered to patients having a history of cardiovascular disease. Since a high proportion of patients afflicted with paralysis agitans also have a history of arteriosclerosis the use of decarboxylase inhibitors to reduce dosage levels of 3,4-dihydroxyphenyl- 1 -alanine is limited.

We have found that the anti-paralysis agitans symptom activity of 3,4-dihydroxyphenyl-[-alanine is potentiated when administered concurrently with a benzodiazepine compound. As a result, the required dose of 3,4-dihydroxyphenyl-l-alanine for alleviating symptoms of paralysis agitans can be reduced by from 25 to percent with the advantage of reduced side effects.

Our finding is surprising since the benzodiazepines do not themselves bring about a lessening of symptoms of paralysis agitans. Furthermore, the benzodiazepines are not known to inhibit the normal metabolism of dopamine, as occurs with the decarboxylase inhibitors.

The method and compositions of our invention are particularly advantageous because the benzodiazepines are generally not contraindicated in the presence of a history of cardiovascular disease. In addition, we have found the combination of 3,4-dihydroxyphenyll-alanine and benzodiazepine to be less toxic than the combination of 3,4-dihydroxyphenyl-l-alanine and a decarboxylase inhibitor such as, for example, imipramine or tranyl cypromine or an antidepressant; see for example, Proctor et al., Arch. Int. Pharm., 163, 87, (1966) reporting on the potentiation of lethality of 3,4-dihydroxyphenyl-l-alanine when administered to aggregated mice with monoamine oxidase inhibitors and a similar result obtained when 3,4-dihydroxyphenyl-l-alanine was administered with an antidepressant [Johnson et al., Current Ther. Res., 12, 402, (1970)].

SUMMARY OF THE INVENTION The invention comprises in the treatment of paralysis agitans by administering a compound selected from 3,4-dihydroxyphenyll -alanine, a hydrate thereof and a pharmaceutically acceptable acid addition salt thereof, to a human afilicted with paralysis agitans the improvement which comprises co'administering a potentiating amount of a benzodiazepine compound having sedative-hypnotic and anxiolytic activity The invention also comprises a unit dose pharmaceutical composition which comprises an effective amount of a compound selected from 3,4-dihydroxyphenyl-lalanine, a hydrate thereof and a pharmaceutically acceptable acid addition salt thereof; for treatment of paralysis agitans with a potentiating amount of a benzodiazepine compound in combination with a pharmaceutical carrier. The compositions of the invention are particularly useful for treating humans afflicted with paralysis agitans.

DETAILED DESCRIPTION OF THE INVENTION The improved method of the invention is carried out by co-administering with a compound selected from 3.4-dihydroxyphenyl- 1 -alanine, a hydrate thereof and a pharmaceutically acceptable acid addition salt thereof; a potentiating amount of a benzodiazepine having sedativehypnotic and anxiolytic activity. A potentiating amount is defined to mean that amount which effects a reduction in the amount of 3,4-dihydroxyphenyl-l-alanine, hydrate or salt thereof, required to alleviate the symptoms of paralysis agitans in an afflicted human. In

general, a potentiating amount is within the range of from about 0.001 mg./kg. to about 1.0 mg./kg. of body weight of the recipient on a daily basis. Of course, the optimum dosage (potentiating amount) of benzodiazepine compound will be varied according to the specific benzodiazepine compound employed. In general, however, the potentiating amount of a given benzodiazepine compound is within the range of from about percent to about 50 percent of the dosage usually employed to obtain an anxiolytic (anxiety relieving) effect in adult humans.

Benzodiazepine compounds having sedative-hypnotic and anxiolytic (anxiety reducing) properties are a well defined class of compounds which may be-broadly characterized as central nervous system depressants. Illustrative of benzodiazepine central nervous system depressants are benzodiazepine compounds of the general formula:

I I l N==C T N-R R N=C s C H R 3, H R 0 (ll) and their pharmaceutically acceptable acid addition salts wherein R represents hydrogen, lower alkyl, lower alkenyl, hydroxy-substituted lower alkyl or lower alkoxysubstituted lower alkyl; R represents hydrogen or lower alkyl; R represents phenyl, halophenyl, nitrophenyl or lower alkoxyphenyl and R and R each represent hydrogen, halogen or lower alkyl. The compounds (II) are well known as is their preparation (see, for example, US. Pat. No. 2,893,992). Illustrative of the compounds of formula (II are 7-chloro-2- methylamino-5-phenyl-3H-1,4-benzodiazepine 4- oxide; 7-chloro-2-methylamino-5-phenyl3H-l ,4-benzodiazepine 4-oxide; 7-bromo-2-amino-5-phenyl-3H- l ,4-benzodiazepine 4-oxide; and 7-chloro-2- methylamino-5-phenyl-3l-I-1 ,S-benzodiazepine 4-oxide hydrochloride and the like which are generally employed in the method of this invention at a dosage of from about 0.01 mg. to about 1.0 mg. per kilogram of body weight of the recipient on a daily basis;

2. the well known 5-monocyclic aryl-l ,4-benzodiazepin-2ones of formula:

(Ill) 3-acetoxy-1,3-dihydro-5-phenyl-2I-l-l ,4-benzodiaze- I pin-2-one; 3-acetoxy-7-chloro-1 ,3-dihydrol -methyl-5-phenyl- 2I-l-l ,4-benzodiazepin-2-one; 3-acetoxy-7-bromo5 (p-chlorophenyl)- l ,3-dihydro- 2I-I-l ,4-benzodiazepin-2-one; 3-acetoxy-7-chloro-l ,3-Dihydro-5-( 2-thienyl )-2H- 1 ,4-benzodiazepin-2-one; 7-chloro-3-( a-chloroacetoxy)- l ,3-dihydro-5-phenyl- 2H-l ,4-benzodiazepin-2-one; 3-benzoxy-7-chloro-l ,3-dihydro-5-phenyl-2H-l ,4-

benzodiazepin-Z-one; 7-chlorol ,3-dihydro-3-ethoxy-5-phenyl-2H, l ,4-benzodiazepin-Z-one; 7-chlorol ,3-dihydro-3-hydroxy-5-phenyl-2H- l ,4-

benzodiazepin-Z-one; 7-chlorol ,3-dihydro-3-hydroxyl -methyl-5-phenyl- 2I-l-l ,4-benzodiazepin-2-one; 7-chloro-5-(o-chlorophenyl l ,3-dihydro-3-hydroxy- 2I-I-l ,4-benzodiazepin-2-one; 7-chloro-5-( o-chlorophenyl )-l ,3-dihydro-3-hydroxyl-methyl-2H-l ,4-benzodiazepin-2-one; 7-chlorol ,3-dihydrol-methyl-5-phenyl-2H- l ,4-

benzodiazepin-Z-one and the like, which may be given according to the method of this invention in doses of from about 0.01 mg. to about 1.0 mg. per kilogram body weight of the recipient on a daily basis;

3. the oxazinobenzodiazepines such as those illustrated by the formula:

the recipient on a daily basis;

7. the 3-alkyl-7-phenylpyrimido l,2-a][ l,4]-benzodiazepin-l [I-I]-one compounds of formula:

(VIII) and their pharmaceutically acceptable acid addition salts, wherein R is hydrogen, lower alkyl, hydroxy or acetoxy; R R R and R are each selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, sulfonamido, amino, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylaminoor dialkylamino in which the carbon moiety is of l to 3 carbon atoms, inclusive per alkane radical; R is hydrogen, lower alkyl, phenyl or benzyl; and X is oxygen, sulfur or the group =NH.

The compounds (VIII) are -well known as is their preparation; see, for example US. Pat. No. 3,734,912. Illustrative of the compounds (VIII) are 9-chloro-3-methyl-7-phenylpyrimido[ 1,2-

a][ l ,4]benzodiazepinl 5H)-one;

3-methyl-9-nitro-7-phenylpyrimido[ l ,2-a][ 1,4]benzodiazepin- 1 (5H )-one;

9-chloro-3-methyl-7-phenylpyrimido[ 1,2-

a][ l,4]benzodiazepin-l-(5H)-thione and the like, all of which may be given according to the method of this invention on a dosage schedule of from about .001 mg. to about 0. l mg. per kilogram of body weight of the recipient on a daily basis.

preferred benzodiazepines for use in the method of the invention are those of group (2.) above having the formula (III). Most preferred is 7-chloro-l,3-dihydrol-methyl-S-phenyl-ZH- l ,4-benzodiazepin-2-one.

As used herein, the term lower alkyl means alkyl of l to 3 carbon atoms, inclusive. The term lower alkenyl means alkenyl of l to 3 carbon atoms, inclusive. The tenn hydroxy-substituted lower alkyl means lower alkyl as previously defined wherein a hydrogen atom has been replaced with a hydroxy group. The term lower alkoxy-substituted lower alkyl means lower alkyl as defined above wherein a hydrogen atom has been replaced with a lower alkoxy group of formula:

Olower alkyl The term lower alkoxyphenyl is used herein to mean phenyl wherein a hydrogen atom has been replaced with a lower alkoxy group as shown above. The term halogen is used in its conventional sense as embracive of chlorine, bromine, iodine and fluorine.

The tenn halogen-substituted lower alkoxy means lower alkoxy as defined above wherein a hydrogen atom has been replaced with a halogen atom. The term phenoxy means the moiety of formula:

O---phenyl; and the term benzyloxy means the moiety of formula:

OCH:-phenyl.

12 The 'term alkylthio is used herein to mean the moiety of formula:

Salkyl wherein alkyl has the stated carbon content. The term alkylsulfinyl, means the moiety of formula -SOalkyl; wherein alkyl has the stated carbon content. The term alkylsulfonyl as used herein means the moiety of formula: i

SO alkyl wherein alkyl has the stated carbon content; and the term dialkylamino means the monovalent moiety of formula:

wherein alkyl has the stated carbon content. The term lower alkanoyl as used herein means the group of formula:

C-lower alkyl wherein lower alkylis as defined above.

The benzodiazepine compounds may be administered according to the method of the invention in their conventionally available pharmaceutical dosage forms. Such dosage forms are well known and are represented by capsules, tablets, powders, granules, syrups, dispersions, suspensions, parenteral solutions, injectable suspensions, suppositories and like dosage forms.

Preferably, the benzodiazepine compound is compounded with the 3,4-dihydroxyphenyl-l-alanine or a hydrate or an acid additionsalt thereof in an orally administrable dosage form, to obtain a composition of the invention. Thus compositions of the invention comprise solid and liquid pharmaceutical preparations containing potentiating amounts of benzodiazepines and effective amounts of 3,4-dihydroxyphenyll-alanine or a hydrate or an acid addition salt thereof in' such proportions that-together they constitute the essential active ingredients for alleviating the symptoms of paralysis agitans in humans. The solid oral compositions may be in the fonn of tablets, scored or unscored, coated and uncoated; capsules, hard and soft; powders; granules; pills; (enteric coated tablets, capsules or pills); and the like. Solid diluents and carriers for solid oral compositions of the invention are those conventionally employed for such compositions and are selectedfrom the group consisting of lipids, carbohydrates, proteins and mineral solids, for example starch, sucrose, kaolin, dicalcium phosphate, gelatin, acacia, corn syrup, corn starch, talc and the like. 7

Tablets contain the essential active'ingredients in the required amount with pharrnaceutically acceptable diluents, excipients, binders, disintegrators and lubricants. The essential active ingredients are preferably mixed with a carbohydrate diluent, for example starch and lactose; a mineral solid, for example terra alba (calcium sulfate) and dicalcium phosphate or the like, to form a basic powder mixture. The said mixture may be granulated by wetting with aprotein binder such as gelatin solution, a carbohydrate such as starch paste, syrup, or acacia mucilage; and screened. As an alternative to granulating, the mixture may be slugged and the slugs broken down into granules prior to formation of the tablets. A carbohydrate disintegrator, for example corn starch, is advantageously added at the time of forming the basic mixture. A lubricant, for example a lipid such as stearic acid, a stearate salt and mineral oil; a mineral solid such as talc; and the like, is used to prevent sticking of the mixture to the tablet-fanning dies. The tablets may be coated or uncoated. Coatings may be a sealing coat of shellac, a taste-disguising carbohydrate coating such as sugar and methyl cellulose or a lipid polish coating of, for example, camauba wax. Coatings may also comprise (a) lipid type coatings of a semi-permeable nature for delaying absorption of the essential active ingredients to provide sustained action, or (b) enteric substances such as styrene maleic acid copolymer and cellulose acetate phthalate to resist release of the essential active ingredients in the stomach and permit release in the upper intestine.

Capsules for oral use comprise the essential active ingredients in combination with a pharmaceutically acceptable diluent or excipient and a formed gelatin enclosure for the composition. The capsules may be in the fonn of soft capsules enclosing the active ingredients in the required amount with suitable diluents, for example edible oils. The diluents for hard capsules comprise mineral solids, for example talc, dicalcium phosphate, and the like; carbohydrates, for example starch and lactose and, as required, lubricants, for example stearate salts.

Powders may be advantageously and conveniently prepared by comminuting the essential active ingredients in the required amount and mixing with a pharmaceutically acceptable diluent; for example an edible carbohydrate such as starch, advantageously including sweetening and flavoringagents, for example sugar or flavoring oils.

Liquid oral compositions of the invention may be in the form of dispersions, suspensions, elixirs, and syrups.

Dispersions may be prepared in glycerol, propylene glycol, liquid polyethylene glycols, and mixtures thereof, and in edible oils. Under ordinary conditions of storage and use such preparations contain a preservative to prevent the growth of microorganisms. Likewise, sweetening, coloring, and flavoring agents may be added.

Suspensions are prepared in an aqueous vehicle containing diluents, flavors and preservatives as desired. Advantageously the suspensions contain suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, acacia, polyvinyl pyrrolidone, polyvinyl alcohol and the like.

Syrup compositions of the invention contain the essential active ingredient in the required amount in an aqueous medium containing a sweetening agent, for example, sugar. Colors, flavors and preservatives are added for convenient storage and use.

It is especially advantageous to compound the compositions of the invention in unit dosage form for ease of administration and uniformity ofdosage.

The tenn dosage unit form as used in this specification and in the claims refers to physically discrete units suitable as unitar dosages for human subjects, each unit containing a predetennined quantity of the essential active ingredients, i.e.; an effective amount of 3,4-dihydroxyphenyl-l-alanine for treating paralysis agitans and a potentiating amount of a benzodiazepine as illustrated above, calculated to produce the desired effect in combination with the required pharmaceutical means which adapt said ingredient for systemic admin- 14 istration. The aforesaid carriers, vehicles, diluents, excipients, preservatives, isotonic agents and the like constitute the pharmaceutical means which adapt the preparations for systemic administration.

The pharmaceutical dosage unit formsare prepared in accordance with the preceding general description to provide from about mg. to about 500 mg. of 3,4-dihydroxyphenyl-l-alanine and a hydrate or an acid addition salt thereof and from about 0.5 mg. to about 5 mg. of benzodiazepine potentiator per dosage unit form as the essential active ingredients. The number of units given in treating specific cases of paralysis agitans must be, of course, related to a number of variables such'as age, sex and patient involved. The response of a given patient is readily observed and the physician may adjust dosage frequency according to his observations of response, side effects, and like considerations considering the nature of the disease being treated.

When desired, other active ingredients normally employed in treating paralysis agitans, such as, for example apomorphine, may also be compounded with the pharmaceutical compositions of the invention.

The following examples set forth the best mode contemplated by the inventors of making and using the invention but are not to be construed as limiting.

EXAMPLE 1 Oral Tablets One thousand oral tablets, each containing 250 mg. of 3,4-dihydroxyphenyl-l-alanine and 5 tug. of I 7- chlorol ,3-dihydrol -methyl-5-phenyl-2H- l ,4-benzodiazepin-Z-one are prepared as follows:

3,4-dihydroxyphenyl-l-alanine 250 gm. 7-chloro-l ,B-dihydro- 1 -methyl- 5-phei1yl-2H-l,4-benzodiazepin-2-nne 5 gm. lactose 200 gm. microcrystalline cellulose NF 50 gm. starch 5 gm. magnesium stearate powder I gm.

The ingredients are thoroughly mixed and slugged. The slugs are broken down by forcing through a screen and the resulting granules are then compressed into tablets.

From one to four of the above tablets may be given one to four times daily to an adult suffering from paralysis agitans. During the course of treatment, akinesia symptoms are ameliorated.

EXAMPLE 2.

Oral Hard-filled Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 500 mg. of 3,4-dihydroxyphenyl-l-alanine and 5.0 mg. of 7-chloro-l,3- dihydro-l -methyl-5-phenyl-2H- 1 ,4-benzodiazepin- 2-one are prepared from the following ingredients:

3,4-dihydroxyphenyl-l-alanine 500 gm. 7-chloro-l,3-dihydro-1-methyl- 5-p henyl-2H- l ,4-benzodiazepin- 2-one 5 gm. lactose 200 gm. talc 25 gm. magnesium stearate 2 gm.

The finely powdered materials are mixed thoroughly, then filtered into hard gelatin capsules of appropriate 15 size.

A satisfactory clinical response is obtained in adults suffering from paralysis agitans when given one to four of the above capsules one to four times a day.

EXAMPLE 3.

Soft Elastic Capsules One-piece soft elastic capsules for oral use, each containing 250 mg. of 3,4-dihydroxyphenyl-l-alanine and 5 mg. of 7-chloro-l,3-dihydro-l-methyl-5-phenyl- 2H-l,4-benzodiazepin-2-one as the essential active ingredients are obtained by first dispersing the active ingredients in sufficient corn oil to render the material capsulatable and then encapsulating an appropriate volume in gelatin by conventional methods.

One to four capsules give 2 to 4 times daily is useful in the treatment of moderate paralysis agitans in humans.

EXAMPLE 4.

An aqueous oral preparation containing in each teaspoonful (5 ml.) 250 mg. of 3,4-dihydroxyphenyll -alanine and 5 mg. of 7-chloro-l,3 dihydro-l-methyl-5- phenyI-ZH-I,4-benzodiazepin-2-one is prepared from the following:

3,4-dihydroxyphenyl-l-alanine 250 gm. 7-chloro-l ,3-dihydrol -methyl-5- phenyl-ZH-l,4-benzodiazepin2-one 5 gm. glycerin 2,000 ml. tragacanth powder 50 gm. propylparabcn 3.0 gm. sucrose 6.5 gm. orange oil flavor 5.0 gm. deionized water q.s. 5,000 ml.

The above suspension, when given on a dosage schedule of one to two teaspoonfuls, 2 to 4 times daily, to a patient suffering from paralysis agitans, ameliorates symptoms of akinesia.

EXAMPLE 5.

Suppositories One thousand suppositories, each weighing 2.0 gms. and containing 250 mg. of 3,4-dihydroxyphenyl-l-alanine with 5 mg. of 7-chloro-l,3-dihydro-l-methyl-5- l6 phenyl-ZH-l ,4-benzodiazepin-2-one are prepared from the following ingredients:

3,4-dihydroxyphenyl-l-alanine 250 gr.

5 7-chlorol .3-dihydro 1 -methyl-5- phenyl-2H1,4-benzodiazepin-2-one 5 gm. polyethylene glycol 1540 500 gm. polyethylene glycol 6000 L000 gm. polyethylene glycol 400 250 gm.

1O Suspend the active ingredients in the polyethylene EXAMPLE 6.

Similarly, following the procedures of Examples 1-5 supra., but replacing the benzodiazepine active ingredient as used therein with potentiating amounts of other compounds having one of the formulae ll-VIII, supra, as illustrated previously, therapeutic compositions are obtained having use in the alleviation of the symptoms 25 of paralysis agitans when administered 'to humans afflicted with suchdisease,

I claim:

l. A method of treatment of paralysis agitans comprising administering from about 250 mg. to about 500 mg. of a compound selected from the group consisting of 3,4-dihydrox'yphenyl-l alanine, a hydrate thereof, or a pharmaceutically acceptable acid addition salt thereof and the co-administering of a potentiating dose of 7-chloro-' l ,3-dihydrol -methyl-5-phenyl- 2H-l ,4- benzodiazepine-Z-one in an amount of from about 1 mg. to about 5 mg. to a human afflicted with paralysis agitans. v

2. A unit dose pharmaceutical composition which consists essentially of from about 250 mg. to about 500 mg.-f a compound selected from the group consisting of 3,4-dihydroxyphenyl-l -alanine,a hydrate thereof, or a pharmaceutically acceptable acid addition salt thereof and from about '1 mg. to about mg. of 7- chloro-l ,3-dihydrol-methyl-S-phenyl-ZH- l ,4-benzodiazepine-Z-one. 

1. A METHOD OF TREATMENT OF PARALYSIS AGITANS COMPRISISNG ADMINISTERING FROM ABOUT 250 MG. TO ABOUT 500MG. OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3,4-DIHYDROXYPHENYL-I-ALANINE, A HYDRATE THEREOF, OR A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF AND THE CO-ADMINISTERING OF A POTENTIATING DOSE OF 7-CHLORO-1,3-DIHYDRO-1-METHYL-5PHENYL-2H-1,4-BENZODIAZEPINE-2-ONE IN AN AMOUNT OF FROM ABOUT 1 MG. TO ABOUT 5 MG. TO A HUMAN AFFLICTED WITH PARALYSIS AGITANS.
 2. A unit dose pharmaceutical composition which consists essentially of from about 250 mg. to about 500 mg. of a compound selected from the group consisting of 3,4-dihydroxyphenyl-1-alanine, a hydrate thereof, or a pharmaceutically acceptable acid addition salt thereof and from about 1 mg. to about 5 mg. of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one. 